According to the findings of a clinical trial safety study published in the January issue of the Chest, Tiotropium, a long-acting anticholinergic was associated with a reduction in the risk of all-cause mortality, cardiovascular (CV) mortality, and CV events.

Increased risk for CV morbidity and mortality is a consequence of COPD. The objective of this study was to evaluate the CV profile of tiotropium. The tiotropium clinical trial program described in this report signify a substantial database of 19,545 patients studied in randomized, double-blind, parallelgroup, placebo-controlled trials for up to 4 years. Inclusion/exclusion criteria were similar, including spirometry confirmed COPD, ≥10 pack-year smoking, and age ≥ 40 years. Incidence rates (IRs) were calculated from the total number of patients with an event divided by total time at risk. Rate ratios (RRs) and 95% CI for tiotropium/placebo were calculated. IRs were determined for all-cause mortality and selected CV events, including a composite CV end point encompassing CV deaths, nonfatal myocardial infarction (MI), nonfatal stroke, and the terms sudden death, sudden cardiac death, and cardiac death.

Of 19,545 patients from 30 trials, 8,699 patients were randomized with placebo and 10,846 with tiotropium. Cumulative exposure to study drug was 13,146 (tiotropium) and 11,095 (placebo) patient-years. For all-cause mortality, the IR was 3.44 (tiotropium) and 4.10 (placebo) per 100 patient-years (RR [95% CI] = 0.88 [0.77-0.999]). IR for the CV end point was 2.15 (tiotropium) and 2.67 (placebo) per 100 patient-years (RR [95% CI] = 0.83 (0.71-0.98]). The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 (tiotropium) and 1.24 (placebo) per 100 patient-years (RR [95% CI] = 0.77 [0.60-0.98]). For total MI, cardiac failure, and stroke the RRs (95% CI) were 0.78 (0.59-1.02), 0.82 (0.69-0.98), and 1.03 (0.79-1.35), respectively.

This analysis of the large tiotropium database indicates a reduced risk for CV events, CV mortality, and all-cause mortality. There were also reductions in the overall risk for serious and fatal lower respiratory events.

Chest 2010; 137(1):20–30.

The use of long-acting β-agonist (LABA) drugs has been questioned as it may increase the risk of asthma mortality. A meta-analysis was which included asthma deaths in randomised controlled clinical trials from the database that compared salmeterol with a non-LABA comparator treatment in asthma. The Peto one-step method was used to find out the risk overall (all studies) and in derived datasets based on inhaled corticosteroid (ICS) use.

Researchers studied 35 asthma deaths in 215 studies with 106, 575 subjects. Results show that the odds ratio for risk of asthma mortality with salmeterol was 2.7 (95% CI 1.4-5.3) whereas in 54 placebo controlled studies the risk of death from asthma in patients not prescribed ICS was 7.3 (95% CI 1.8-29.4).

In 127 studies in which patients were prescribed ICS, the risk of asthma death was 2.1 (95% CI 0.6-7.9). In 63 studies in which patients were randomised to receive the combination salmeterol/fluticasone propionate inhaler or ICS, there were no asthma deaths among 22, 600 patients.

This study showed that salmeterol monotherapy in asthma increases the risk of asthma mortality; however this risk is reduced with concomitant ICS therapy. There is no data that salmeterol/fluticasone propionate combination therapy is associated with an increased risk of asthma mortality, although this interpretation is limited by the low statistical power of available studies.

Thorax 2010; 65:39-43.

A cohort study published in the January 2010 issue of the Respiratory Medicine showed that treatment of exacerbations out of the hospital was associated with a decreased risk of readmission.

Obstructive lung disease is a leading cause of morbidity and mortality worldwide. The study aimed at quantifying the incidence of readmission in chronic obstructive lung disease and indentifying determinants for hospital readmission.

A cohort study was conducted using the PHARMO record linkage system, which included demographic details and complete medication histories of more than two million community-dwelling residents in the Netherlands from 1985 onwards. Adult users of inhaled corticosteroids (ICS) with an admission for obstructive lung disease were included in the study. The outcome parameter was readmission within a follow-up period of one year.

605 ICS users were identified with an admission for chronic obstructive lung disease, of which 132 patients were readmitted. Readmission was associated with a high Chronic Disease Score (adjusted HR 2.4; 95% CI 1.1-5.3). Patients using short courses of systemic corticosteroids only (adjusted HR 0.5; 95% CI 0.4-0.8) or combined with antibiotics (adjusted HR 0.4; 95% CI 0.2-0.6) were at decreased risk of readmission. The effect of high-dose ICS use varied over time.

Study highlights that occurrence and successful treatment of exacerbations out of the hospital was associated with a decreased risk of readmission, while patients having multiple chronic diseases are at increased risk of readmission for obstructive lung disease. Readmission was associated with high-dose ICS use during 4-6 months follow-up. Researchers say that such patients should be educated and should be invited to consultation more often to be able to detect exacerbation in an early phase and start treatment as early as possible.

Previous studies have suggested a reduced benefit from inhaled corticosteroid (ICS) therapy in asthmatic smokers. A recent study published in the December issue of Chest 2009 indicates that smokers with newly diagnosed asthma are likely to derive a similar benefit from inhaled budesonide as nonsmokers, in terms of lung function.

The objective of this post hoc study was to analyse the effects of low-dose inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma.

Adult patients (age, ≥18 years) in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, a 3-year, randomized, placebo-controlled, double-blind study, were stratified according to their smoking habits. 492 smokers and 2, 432 nonsmokers were randomized with either budesonide (400 mcg daily) or placebo. Changes in concurrent asthma medication were allowed during the study, at the investigator’s discretion, to achieve asthma control.

Asthmatic smokers who received placebo had a greater decline in lung function than asthmatic nonsmokers. Specifically, in the placebo group at 3 years, post-bronchodilator therapy FEV1 declined by 263.9 mL in smokers and by 180.8 mL in nonsmokers. The mean difference was -83.1 mL (p < 0.001).

Budesonide treatment was associated with a statistically significant 3-year increase in post-bronchodilator therapy FEV1 in both groups. The benefit of budesonide over 3 years was 71.5 mL (p = 0.011) in smokers and 46.5 mL (p = 0.001) in nonsmokers. The corresponding effect in pre-bronchodilator therapy FEV1 was 118.1 mL (p = 0.002) in smokers and 72.9 mL (p < 0.001) in nonsmokers. The corresponding effect in pre-bronchodilator therapy FEV1 was 118.1 mL (p = 0.002) in smokers and 72.9 mL (p < 0.001) in nonsmokers.

The investigators report that asthmatic patients who smoke, and are not treated with ICSs, have a greater decline in lung function than asthmatic patients who do not smoke.

The risk of having a first severe asthma-related event was significantly reduced by budesonide therapy (hazard ratio, 0.50; p < 0.001) and no significant difference was seen between smokers and nonsmokers.

The study concludes that at least for changes in FEV1 over time, ICS therapy provides a benefit in both smokers and nonsmokers with mild, persistent asthma. Investigators point out the magnitude of the benefit was numerically (although not significantly) larger in asthmatic patients who smoke.